With advancing age or prematurely in obese children, arterial stiffness increases and has been implicated in the development of hypertension. Because the aortic stiffness transmits higher pressure to the peripheral vasculature, it may also be causally related to the clinical complications of hypertension. Our preliminary studies in normal mice made obese by feeding a diet which is high in fat (30%) and sucrose (30%, HFHS), and is typical of that consumed by many Americans, show an association between increased aortic tone and stiffness present after 2-4 months of diet with systolic hypertension that is present after 10 months, but not after 2 months. At the earlier time point HFHS diet also impairs endothelium-dependent relaxation and increases oxidation of functionally significant aortic smooth muscle cell (SMC) proteins, including the sarcoplasmic reticulum Ca2+ ATPase (SERCA). As SERCA regulates the SMC response to nitric oxide (7NO), this suggests the hypothesis that abnormalities in SMC metabolism and oxidants caused by HFHS diet may impair 7NO function and lead to increased aortic tone and stiffness that may be causally related to the later development of hypertension. Our preliminary studies also show that polyphenols which activate the master metabolic regulator, sirtuin-1 (Sirt1), relax SMC and when added to HFHS diet, prevent both the early abnormalities in aortic tone and oxidants, as well as the late hypertension. This is consistent with the further hypothesis that HFHS diet-induced vascular metabolic abnormalities, oxidants, and stiffness are regulated by Sirt1 in SMC. The 3 aims will 1) test if there is a temporal and potentially causal relationship between the early 7NO dysfunction, increased oxidants, and stiffness of aortic SMC with the later development of systolic hypertension associated with obesity induced by HFHS diet in C57BL6 mice, 2) determine if a Sirt1-activating polyphenol or dietary fat reduction can reverse early metabolic mediators of aortic stiffness and prevent later hypertension, and 3) using transgenic mice with tissue-specific deletion of SMC Sirt1, test if SMC Sirt1 is a potential therapeutic target for improving aortic stiffness and hypertension caused by obesity. PUBLIC HEALTH RELEVANCE: Obesity increases the complications of cardiovascular disease, including aortic stiffness and hypertension. Our studies will determine how oxidants arising from tissue metabolism in obese mice increase aortic stiffness and cause hypertension. As aortic stiffness precedes hypertension, we will test if ameliorating aortic oxidants and stiffness at a younger age can prevent the later development of hypertension.